The role of IL-18 in bone destruction due to cancer metastasis

1. 白细胞介素(IL)-18在转移性肿瘤骨吸收中的作用：(1)IL-18受体在成骨细胞和破骨细胞中的表达：采用免疫组化技术检测IL-18受体在成骨细胞和破骨细胞中的表达。在这些细胞中，IL-18受体成分的mrna也通过逆转录酶聚合酶链反应表达。(2)体外条件下IL-18在破骨细胞骨吸收中的作用：纯化自小鼠的破骨细胞骨吸收与IL-18共培养可抑制破骨细胞骨吸收。(3)体内条件下IL-18在破骨细胞骨反应中的作用：采用裸鼠心脏内注射人乳腺癌细胞MDA-231和骨髓瘤细胞ARH-77建立骨转移模型。IL-18抑制骨转移部位的溶骨性肿瘤生长。(4) IL-18抑制骨破坏的机制：IL-12协同干扰素γ (IFN-γ)的产生可增强IL-18对骨破坏的抑制作用。IL-18在骨关节炎（OA）和类风湿性关节炎（RA）发病机制中的作用。(1) IL-18在OA软骨降解中的作用：IL-18与OA滑液中前列腺素（PG）E^2有较强的相关性。IL-18通过PGE^2释放在OA发病机制中起重要作用。(2) RA中IL-18的产生：IL-18已被报道为类风湿关节炎（RA）的促炎细胞因子。我们通过刺激可溶性Fas配体来测定IL-18在CD14+巨噬细胞中的释放。总之，在转移性骨肿瘤、OA和RA等疾病中，靶向IL-18似乎是防止骨破坏和关节软骨退化的重要治疗方法。

1. The role of Interleukin (IL)-18 in bone resorption due to metastatic cancer :(1) Expression of IL-18 receptor in osteoblast and osteoclast : IL-18 receptor was detected in both osteoblast and osteoclast by immunohistochemical technique. The presence of mRNAs for IL-18 receptor components was also expressed by reverse transcriptase polymerase chain reaction in these cells.(2) The role of IL-18 in osteoclastic bone resporption in vitro condition : Osteoclastic bone resorption, purified from mice, was inhibited in co-culture with IL-18.(3) The role of IL-18 in osteoclastic bone resporption in vivo condition : The model of bone metastasis was established by an intracardiac injection of human breast cancer cells (MDA-231) and myeloma cell (ARH-77) in nude mice. IL-18 inhibited osteolytic growth of the cancer at bone metastatic sites.(4) The mechanism of the suppression of bone destruction by IL-18 : This activity could be synergistically enhanced by IL-12 followed by interferon gamma (IFN-γ) production.2. The role of IL-18 in pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA).(1) The role of IL-18 in cartilage degradation of OA : There was a relatively strong correlation of IL-18 to prostaglandin (PG)E^2 in the synovial fluid of OA.IL-18 plays an important role in the pathogenesis of OA through the PGE^2 release.(2) Production of IL-18 in RA : IL-18 has been reported as a proinflammatory cytokine in rheumatoid arthritis (RA). We determined the IL-18 release in CD14+ macrophages by stimulation of soluble Fas ligand.In conclusion, targeting the IL-18 appears to be an important therapeutic approach to prevent bone destruction and articular cartilage degradation, in diseases such as metastatic bone tumor, OA, and RA.